Abstract Lung infections are a major contributor to the worldwide public health burden, resulting in significant morbidity and mortality, the latter of which has not improved since the discovery of antibiotics. Successful recovery from pneumonia requires both host immune resistance and tissue resilience, the latter of which serves to counter damage elicited by the invading pathogen or the host itself. At present, there is a major knowledge gap regarding the biological pathways controlling lung resilience that lead to either successful recovery or the development of pneumonia-related complications such as ARDS. Here we propose Lectin-like oxidized low- density lipoprotein receptor-1 (LOX-1) as a potential mediator of acute pulmonary inflammation and tissue homeostasis during pneumonia. LOX-1 is a class E scavenger receptor that responds to multiple inflammatory ligands including oxLDL, advanced glycation end products, and activated platelets, and is primarily known for its role in promoting endothelial inflammation in the setting of atherosclerosis. Our preliminary results show for the first time that both membrane-bound LOX-1 and its soluble, potentially anti-inflammatory counterpart (sLOX-1) are markedly increased at the transcriptional and translational level in response to pneumonia caused by Gram-negative bacteria. LOX-1 also decreases on the cell surface of lung-recruited neutrophils, and this occurs concomitantly with a significant increase in sLOX-1 recovered from pneumonic airspaces. Interestingly and contrary to known prototypical inflammatory role of LOX-1, we have found that antibody- mediated inhibition of lung LOX-1 in the airspaces, results in exaggerated tissue injury and inflammation following E. coli pneumonia, with no effect on bacterial clearance or leukocyte recruitment. This discovery reveals a novel, tissue-protective role for intra-pulmonary LOX-1 during pneumonia, potentially mediated by neutrophil delivery of soluble LOX-1 to the airways. However, the sources, targets, and biological significance of pulmonary LOX-1 are currently unknown. Thus, we propose the central hypothesis that neutrophils deliver LOX-1 to pneumonic airspaces in order to limit inflammatory tissue injury. This hypothesis will be tested by pursuing the following aims: 1) To elucidate the primary sources of pulmonary LOX-1 and its influence on lung injury during pneumonia; and 2) To test the hypothesis that neutrophil-derived soluble LOX-1 mitigates acute pulmonary inflammation. Results from our investigations will be the first to reveal when, whether, and why lung LOX-1 impacts pneumonia outcome, perhaps paving the way for novel clinical interventions in at risk patients.